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Pseudaminic acid (Pse5Ac7Ac) is a nonmammalian sugar present on the cell surface of a number of bacteria including Pseudomonas aeruginosa, Campylobacter jejuni, and Acinetobacter baumannii. However, the role Pse5Ac7Ac plays in host–pathogen interactions remains underexplored, particularly compared to its ubiquitous sialic acid analogue Neu5Ac. This is primarily due to a lack of access to difficult to prepare Pse5Ac7Ac glycosides. Herein, we describe the in vitro biocatalytic transfer of an activated Pse5Ac7Ac donor onto glycosyl acceptors, enabling the enzymatic synthesis of Pse5Ac7Ac-containing glycosides. In a chemoenzymatic approach, chemical synthesis initially afforded access to a late-stage Pse5Ac7Ac biosynthetic intermediate, which was subsequently converted to the desired CMP-glycosyl donor in a one-pot two-enzyme process using biosynthetic enzymes. Finally, screening a library of 13 sialyltransferases (SiaT) with the unnatural substrate enabled the identification of a promiscuous inverting SiaT capable of turnover to afford β-Pse5Ac7Ac-terminated glycosides.
Bibliographical noteFunding Information:
We thank Dr Simon Charnock of Prozomix Ltd for supplying SiaTs used in the pseudaminyltransferase activity screen as well as Dr. Ed Bergstrom and The York Centre of Excellence in Mass Spectrometry. The York Centre of Excellence in Mass Spectrometry was created thanks to a major capital investment through Science City York, supported by Yorkshire Forward with funds from the Northern Way Initiative and subsequent support from EPSRC (EP/K039660/1; EP/M028127/1). This work was supported by The University of York, the BBSRC (BB/M02487X/1, T.K.), the EPSRC (EP/P030653/1. D.B.), and The Rosetrees Trust. M.C.G. thanks the European Research Council (ERC-COG: 648239) and BBSRC (BB/M028976/1, J.M.P. and H.L.).
Copyright © 2020 American Chemical Society.
- chemoenzymatic synthesis
- pseudaminic acid glycosides
- sialic acid mimics
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- 2 Finished
1/07/15 → 31/12/20